Clinical characteristics: The spectrum of propionic acidemia (PA) ranges from neonatal onset to late-onset disease. Neonatal-onset PA, the most common form, is characterized by a healthy newborn with poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Without prompt diagnosis (often through newborn screening) and management, this is followed by progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death. It is frequently accompanied by metabolic acidosis with anion gap, lactic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias.

Individuals with late-onset PA may remain asymptomatic and suffer a metabolic crisis under catabolic stress (e.g., illness, surgery, fasting) or may experience a more insidious onset with the development of multiorgan complications including vomiting, protein intolerance, failure to thrive, hypotonia, developmental delays or regression, movement disorders, or cardiomyopathy.

Isolated cardiomyopathy can be observed on rare occasions in the absence of clinical metabolic decompensation or neurocognitive deficits.

Manifestations of neonatal-onset and late-onset PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, and chronic kidney disease. Other rarely reported complications include optic atrophy, sensorineural hearing loss, and premature ovarian insufficiency.

Diagnosis/testing: PA is caused by deficiency of propionyl-coenzyme A carboxylase (PCC), the enzyme that catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA. Newborns with PA tested by expanded newborn screening (NBS) have elevated C3 (propionylcarnitine). Testing of urine organic acids in persons who are symptomatic or those detected by NBS reveals elevated 3-hydroxypropionate and the presence of methylcitrate, tiglylglycine, propionylglycine, and lactic acid. Testing of plasma amino acids generally reveals elevated glycine. Confirmation of the diagnosis relies on detection of biallelic pathogenic variants in PCCA or PCCB by molecular genetic testing, or detection of deficient PCC enzymatic activity. In individuals with equivocal molecular genetic test results, a combination of enzymatic and molecular diagnostics may be necessary.

Management: Treatment of manifestations: The treatment of individuals with acutely decompensated PA is a medical emergency: treat precipitating factors such as infection, dehydration, vomiting; reverse catabolism by providing intravenous glucose and lipids; manage protein intake to reduce propiogenic precursors; remove toxic compounds using intravenous carnitine, and when necessary nitrogen scavenger medications and/or extracorporeal detoxification; transfer to a center with biochemical genetics expertise and the ability to support urgent hemodialysis, especially if hyperammonemia is present.

Prevention of primary manifestations: Individualized dietary management should be directed by an experienced physician and metabolic dietician to control the intake of propiogenic substrates and to guide increased caloric intake during illness to prevent catabolism, typically by using specialized medical food. Gastrostomy tube placement is an effective strategy to facilitate the administration of medications and nutrition during acute decompensations and to improve adherence in chronic management of PA. Medications may include L-carnitine supplementation to enhance excretion of propionic acid and oral metronidazole to reduce propionate production by gut bacteria. Orthotopic liver transplantation may be indicated in those with frequent metabolic decompensations, uncontrollable hyperammonemia, and/or poor growth.

Prevention of secondary complications: Consistent evaluation of the protein prescription, depending on age, sex, level of physical activity, severity of disorder, and presence of other factors such as intercurrent illness, surgery, and growth spurts to avoid insufficient or excessive protein intake is necessary. Excessive protein restriction or overreliance on medical foods can result in deficiency of essential amino acids and impaired growth, as well as catabolism-induced metabolic decompensation.

Surveillance: Monitor affected individuals with a catabolic stressor (fasting, fever, illness, injury, and surgery) closely to prevent and/or detect and manage metabolic decompensations early. Regularly assess: (1) growth, nutritional status, feeding ability, and psychomotor development; (2) vision and hearing; (3) cardiac function for signs of cardiomyopathy and prolonged QT interval; (4) metabolic status by monitoring routine chemistries, plasma ammonia, plasma amino acids, and plasma carnitine levels; (5) complete blood count; and (6) kidney function.

Agents/circumstances to avoid: Avoid prolonged fasting, catabolic stressors, and excessive protein intake. Lactated Ringer's solution is not recommended in individuals with organic acidemias. In individuals with QT abnormalities, avoid medications that can prolong the QT interval. Neuroleptic antiemetics (e.g., promethazine) can mask symptoms of progressive encephalopathy and are best avoided.

Evaluation of relatives at risk: Testing of at-risk sibs of an affected individual is warranted to allow for early diagnosis and treatment.

Genetic counseling: PA is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PCCA or PCCB pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the PCCA or PCCB pathogenic variants have been identified in an affected family member, molecular genetic carrier testing of at-risk relatives and prenatal/preimplantation genetic testing are possible.